ArticleNature chemical biology2021
ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR.
Article in Nature chemical biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 31 citations in OpenAlex.
- Beyond bystanders: How β cell stress shapes the autoimmune response in T1D.Science translational medicine · 2026Review
- Messenger RNA delivery to islet β cells using conjugated lipid nanoparticles.Cell reports. Medicine · 2026Article
- Review
- Pathophysiology of reactive oxygen species (ROS).Archives of toxicology · 2026Review
- Pharmacologic inhibition of IRE1α-dependent decay protects alveolar epithelial identity and prevents pulmonary fibrosis in mice.The Journal of clinical investigation · 2025Article
- Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.Nature reviews. Endocrinology · 2025Review
- Endoplasmic Reticulum Stress in Cancer.MedComm · 2025Review
- IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity.Cell reports · 2025Article
- Endoplasmic reticulum stress in lung cancer.Frontiers in oncology · 2025Review
- Discovery of a Compound That Inhibits IRE1αACS chemical biology · 2024Article
- Beyond UPR: cell-specific roles of ER stress sensor IRE1α in kidney ischemic injury and transplant rejection.Kidney international · 2023Review
- Oridonin promotes endoplasmic reticulum stress via TP53-repressed TCF4 transactivation in colorectal cancer.Journal of experimental & clinical cancer research : CR · 2023Article
- Selective inhibitors of SARM1 targeting an allosteric cysteine in the autoregulatory ARM domain.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Small-molecule discovery in the pancreatic beta cell.Current opinion in chemical biology · 2022Review
- Conformation-tunable ATP-competitive kinase inhibitors.Chemical communications (Cambridge, England) · 2022Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. However, under high or chronic ER stress, the UPR triggers apoptosis. This cell fate dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1α. We previously found that the RNase of IRE1α can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors, partial antagonists of IRE1α RNase (PAIRs), that partially antagonize the IRE1α RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the helix αC in the IRE1α kinase domain. In insulin-producing β-cells, PAIRs permit adaptive splicing of Xbp1 mRNA while quelling destructive ER mRNA endonucleolytic decay and apoptosis. By preserving Xbp1 mRNA splicing, PAIRs allow B cells to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory 'sweet spot', achieved by PAIR-bound IRE1α, captures a desirable conformation for drugging this master UPR sensor/effector.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.